Tobacco smoke contains pro-oxidant substances, mutagens and carcinogens (1) and evidence linking cigarette smoke exposure with cardiovascular disease and cancer is clearly present. The primary role of cigarette smoking in coronary artery disease (CAD) is to cause injury to the vascular endothelium by direct cytotoxicity, leading to endothelial dysfunction and atherosclerosis (2). In both animal and human models, several studies have demonstrated that both active and passive cigarette smoke exposure were associated with a decrease in vasodilatory function (3-4). In addition to vasomotor dysfunction, potential pathways and mechanisms for smoking-induced cardiovascular disease are inflammation, platelet dysfunction, alteration of antithrombotic and prothrombotic factors, alteration in fibrinolysis and modification of lipid profile (5). Cessation of smoking (6-9) and antioxidant therapy (10) both improve endothelial function in smokers, suggesting a role for increased levels of oxygen-derived free radicals (11). The precise mechanism of smoking-related endothelial dysfunction is not well understood and is very likely multifactorial. In humans, the situation is even more complex since chronic smokers can cumulate various risks factors for CAD such as obesity, hypertension, dyslipidemia and diabetes, pathologies themselves exacerbated by smoking.
At the cellular level, aging of healthy vascular ECs leads to senescence, a state of permanent growth arrest (12-13). Senescence is characterized by specific changes in cell morphology and gene expression, which reduce EC function (14-15) and thus are proposed to be pro-atherogenic (16-17). Senescence can be triggered by cell divisions that lead to cumulative telomere attrition down to a threshold length at which cells enter the so-called replicative senescence (18). Cellular senescence can also occur prematurely following exposure to multiple types of stress (stress-induced senescence), independently of replicative age, such as oxidative stress (19), DNA damage and mitogenic stress (13).
The atherosclerotic lesion develops through age. It can lead to coronary artery disease (CAD), promoting cardiac ischemia and death. Cardiovascular diseases are associated with numerous risk factors such as aging, diabetes, obesity, hypertension, dyslipidemia but also viral and bacterial infection. The first target of these risk factors, all associated with a rise in oxidative stress, is the vascular endothelium. Vascular endothelial cells (ECs) become dysfunctional before clinical signs of vascular diseases. If a biomarker could predict the level of damage of the endothelium, a clinician could intervene early in the development of the pathology and prevent its outcome, reducing costs for the health system and benefits to the patient.
Hence, there exists a need for a biomarker of vascular endothelial cell abnormal function and senescence. An object of the present invention is therefore to provide a biomarker of vascular endothelial cell abnormal function and senescence.